Medication for psychic disturbances



United States Patent DEDICATION FOR PSYCHIC DISTURBANCES Gilbert Ancel, Neuilly-sur-Seine, France, assignor to Socit dEtudes Scientifiques et lndustrielles de llle-de- France, Paris, France, a society of France No Drawing. Filed Aug. 15, 1961, Ser. No. 131,482

Claims priority, application France Mar. 20, 1961 2 Claims. (Cl. 167-65) The present invention relates to a medication in injection form for psychic disturbances acting rapidly on the psychometric agitation and in which the active element is l -ethyl-bmethyl-propyl carbamate having the following formula:

0 11 O 0 ONE:

The preparation of this compound, also known under the name of :emylcamate, is made by first preparing phenyl ohlorcarbonate by reacting phosgene with phenol which is then reacted in an autoclave with l-ethyl-l-methyl propanol in the presence of liquid ammonia. The l-ethyl-lmethyl-propyl carbamate is thus directly obtained.

When administered orally for treatment of ethylic neurosis, it was observed that LethyI-I-methyl-propy-l carbamate presents a greater activity than Z-mcthyl-Z-N- propy1-1,3-propanediol dicarbamate. These qualities of 1-ethy1-l-methyl-propy1 carb-amalte, however, are not sulficient enough to permit its use in cases of violent psychomotric disturbances needing to be calmed quickly which is notably the case in a crisis of tremens delirium.

A form of 1-ethyl-l-methyl-propyl carbamate assuring its rapid action has been sought for since a long time back and the form naturally considered was by injection. As there is not any question of injecting it in aqueous solution form given the low solubility of l-ethyl-l-methylpropyl carbamate in water (4 gm's. per liter at 20 C.), the solvents of l-ethyl-l-methyl-propyl carbamate were then considered. None of the solvents of a high dissolution quotient is acceptable for human therapy for which a suspension of l-ethyl-l-methyl-propyl carbamate in carboxymethylcellulose also presents no interests. Outside of these general solvents, tests tried by the applicant have shown, besides, that dissolution in propylene glycol brings .about great pain during the injection thus rendering intolerable a treatment repeated various times per day.

Following up his researches, the applicant then observed it possible to dissolve strong proportions of 1-ethyl-. l-methyl-propyl carbamate in isopropyl propylene glycol ether having the following formula 'iSO as shown in the following table Temperature Concentration 40 g./l00 cc soluble soluble. 50 g./100 cc ins0lub1e Do. 60 g./100 do insoluble.

3,692,551 Patented June 4, 1963 Orally LD 50: Mg./kg. Mouse 873 Rat 948 Tolerance tests on rats have shown the daily absorption of 200 rug/kg. during 6 weeks to be well tolerated.

Chronic and subacute toxicity tests of various animals can be thus summarised:

Minimum Animal tolerated Means of Duration dosage in introduction mgJkgJday 200 orally 1 month. 400 do D0. 25 intraperitoneal Do. orally 10 months.

During the pharmacological studies, meprobamate, also known as 2-methyl-2-N-propyl-1,3-propanediol dicarbamate, was used as a comparison control.

Spontaneous motility studies on results observed 1 hour after the absorption of the product given in a 50 mg./ kg. dosage, it must be equally kept in mind, showed a 63% decrease of motility to the advantage of l-ethyl-l-methylpropyl carbamate as against a decrease of only 32% to the advantage of 2-methyl-2-N-pr-opyl-1,3-propanediol dicarbamate, the 2-methyl-2-N-propyl-l,B-propanediol dicarbamate being used as a comparison control.

l-ethyl-l-methyl-propyl carbamate, it should be kept in mind, has a powerful muscular relaxing effect as shown in the following table which condenses the results on the study of the AD 50 and the LD 50 as Well as on the latency time between injection and appearance of the lateral position:

AD 50, LD 50, Num- Thera- Latency Product mgJkg. mgJkg. ber of peutic time, mice index min.

1-ethyl1methylpropyl 550 110 4. 4 3

carharnate. 2-methyl-2Npropyl 600 110 3. 4 35 1,3-propanediol dicarbamate.

Finally, the anticonvulsive effect of l-ethyl-l-methylpropyl carbarnate, given before the injection of convulsive agents such as strychnine and pentamethylene tetrazol, gives the following results:

tests, the products were given 3 and 35 minutes respectively before the convulsive agent.

With electroshock treatment, 10 mice were simultaneously electroshocked and with l-ethyl-l-methyl-propyl carbamate the following results were obtained:

Dosage, Number of mgJkg. animals put Product intraperiin the state toneal of convulsion Cor trols 40/40 l-ethyl-l-methykpropyl carbamate 100 8/10 150 /10 Q-mothy12Npropyl-1, 3-propancdi0l dicar- 100 8/10 bamate. 150 /10 The clinical studies of 1-ethyl-1-methyl-propyl carbamate administered orally showed it to be a powerful tranquilizer respecting precision in gests and skills and having none of the secondary effect found in other similar tranquilizing products, giving neither observed anomalies of the blood formula nor visceral reverberations.

Clinical tests performed by the applicant using a solution in injection form of l-ethyl-l-methyl-propyl carbamate and isopropyl propyleneglycol ether first showed the said product to be well tolerated by dogs; for, by injecting into a new animal weighing 9.5 kg. an ampulla containing 0.50 gr. of l-ethyl-l-methyl-propyl carbam-ate and a sufiicient quantity for a final volume of 1 cc. of isopropyl propyleneglycol ether, no other reactions but a brief loss of consciousness and motor-incoordination were noted. On the other hand, the injection of isopropyl propyleneglycol ether 1 cc. per 8.5 kg.) was very well tolerated by another dog used as control.

In human therapy, 14 patients underwent a treatment of l-ethyl-l-methyl-propyl carbamate dissolved in isopropyl propyleneglycol ether administered parenterally or intravenously as well as intramuscularly. It was observed that l-ethyl-l-methyl-propyl carbamate in injection form under the invention conditions is very well tolerated and that intr-amuscularly it is put into use with facility.

(1) Local tolerance of l-ethyl-l-methyl-propyl carbamate appears to be perfect: no pain at the injection point, no objective sign of local irritation.

(2) General tolerance appears to be equally perfect, for daily doses of 0.50 to 1.50 g. per 24 hours at a variable duration of 3 days to 7 weeks: no albuminuria, no blood formula modification, no anomalies of any of the biological constances. One of the fourteen patients entered with a clinical syndrome and complete biology of icterus gravis during a cirrhosis developed to death.

(3) T herapcutic efiiciency.0f the 14 patients treated, there were only two failures, both having characterized psychotic disturbances one with asocial and psychataxic mental deficiency along with exhibitionism treated Several times in psychiatric services, and the other with hypochondr-iac psychosis along with paranoical delirium.

l-ethyl-l-methyl-propyl carbamate appeared to be inadequate for both these two subjects, the first having to be confined, the second being released a few days later at his own request.

Noted in all the other cases:

A very rapid and constant action,

A manifest sedation of psychomotric agitation,

The eifect appears to be particularly remarkable, in the predeliriums and the ethylic deliriums, at least equal in its intensity as by the chlorpromazine treatment, clearly superior by its excellent tolenance, absence of a tension drop, a better consciousness control.

In conclusion, the solution in injection form prepared according to the invention has given spectacular results, while by oral administration in the form of pills these results have never been either obtained or even suggested.

Intramuscular administration by preference in ampulla form:

l-ethyl-l-methyl-propyl carbamate mg 500 Isopropyl propyleneglycol ether, q.s.p. cc 1 at the rate of 1 to 3 ampullae per day according to attending physicians prescription.

What I claim is:

1. An injection form medication for psychic disturbances comprising a solution of l-ethyl-l-methyl-propyl carbamate having the formula:

0 1-1 000N112 in isopropyl propyleneglycol ether.

2. A tranquilizing medication in injection form for psychic disturbances comprising 500 mg. of 1-ethyl-1- methyl-propyl carbamate dissolved in 1 cc. of isopropyl propyleneglycol ether.

References Cited in the file of this patent Melander: J. of Med. and Pharm. Chem, vol. 1, No. 5, pp. 443-457, 1959. 

1. AN INJECTION FORM MEDICATION FOR PSYCHIC DISTURBANCES COMPRISING A SOLUTION OF 1-ETHYL-1-METHYL-PROPYL CARBAMATE HAVING THE FORMULA: 